The present invention relates to new prostaglandin derivatives. More particularly, the present invention relates to nitrooxyderivatives of prostaglandin amides (also known as prostamides), pharmaceutical compositions containing them and their use as drugs for treating glaucoma and ocular hypertension.
Glaucoma is a disease of the eye characterized by a progressive loss of visual field due to irreversible damage to the optic nerve to the point where, if untreated, may result in total blindness. Glaucoma occurs when an imbalance in production and drainage of fluid in the eye (aqueous humor) increases eye pressure to unhealthy levels. The chief pathophysiological feature of glaucoma is raised intraocular pressure (IOP). The loss of visual field, in one form of primary open angle glaucoma (POAG), is associated with a sustained increase in the intraocular pressure of the diseased eye. Moreover, elevated intraocular pressure without visual field loss is thought to be indicative of the early stages of this form of POAG.
It is known that elevated IOP can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye or increase the fluid drainage, such as beta-blockers, α-agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.
Several side effects are associated with the drugs conventionally used to treat glaucoma. Topical beta-blockers show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia. Topical α-agonists have a fairly high incidence of allergic or toxic reactions; topical cholinergic agents (miotics) can cause visual side effects.
Topical prostaglandin analogs (bimatoprost, latanoprost, travoprost and unoprostone) used in the treatment of glaucoma can produce ocular side effects, such as increased pigmentation of the iris, ocular irritation, conjunctival hyperaemia, iritis, uveitis and macular oedema (Martindale, Thirty-third edition, p. 1445).
U.S. Pat. No. 3,922,293 describes monocarboxyacylates of prostaglandins F-type and their 15β isomers, at the C-9 position, and processes for preparing them; U.S. Pat. No. 6,417,228 discloses 13-aza prostaglandins having functional PGF2α receptor agonist activity and their use in treating glaucoma and ocular hypertension.
WO90/02553 discloses the use of prostaglandin derivatives of PGA, PGB, PGE and PGF, in which the omega chain contains a ring structure, for the treatment of glaucoma or ocular hypertension.
WO00/51978 describes novel nitrosated and/or nitrosylated prostaglandins, in particular novel derivatives of PGE1, novel compositions and their use for treating sexual dysfunctions.
U.S. Pat. No. 5,625,083 discloses dinitroglycerol esters of prostaglandins which may be used as vasodilators, antihypertensive cardiovascular agents or bronchodilators.
U.S. Pat. No. 6,211,233 discloses compounds of the general formula A-X1—NO2, wherein A contains a prostaglandin residue, in particular PGE1, and X1 is a bivalent connecting bridge, and their use for treating impotence.